Extensive efforts have been expended in the search for chemicals that enhance the penetration of therapeutic drugs through human skin. Although such "chemical penetration enhancers (CPEs)" can be valuable in increasing the amount and/or rate of drug delivery, they can also have undesirable effects, including skin irritation and toxicity. A distinct need exists for effective methods to identify new CPEs to provide optimum penetration enhancement with minimum side effects. The primary goal of our proposed research is to integrate non-linear, theory-based quantitative-structure- property-relationship (QSPR) modeling and robust genetic algorithms (GAs) to design improved CPEs. Our basic premise is that novel, effective mathematical models can be developed to describe accurately the relationship between the molecular structure of a chemical and its CPE behavior, and that these models can form the basis for the virtual design of promising molecular structures for use as CPEs. Ultimate benefits of such a design capability include: identifying novel CPEs; reducing the need for expensive and time- consuming experiments; and setting the stage for the synthesis and commercialization of improved CPEs for use by the medical community. The proposed research is both exploratory and developmental in that we shall seek to (a) develop improved molecular-structure-based models for skin permeation and irritation using advanced non-linear modeling, (b) introduce third-generation GAs, to search for, "score," and screen molecules for their value, (c) combine the above models and algorithms into a platform for the development of a seamless capability for effectively and efficiently identifying improved CPEs, and (d) conduct carefully-designed experiments, as needed, to provide data for both database development and validation of CPE efficacy. The research will proceed in two stages. First, new CPE screening models will be developed, based on available data and verified against a drug for which information is already available (nicotine). Second, carefully-selected experimental measurements will be made to expand the existing database to facilitate expansion of these models to a more complex drug (insulin). [unreadable] [unreadable] [unreadable]